Biofilms are defined in the art as structured communities or aggregates of microorganisms (e.g. bacterial cells) in which cells adhere to each other and/or to a living or inert (non-living) surface. These adherent cells are frequently embedded within a self-produced matrix of extracellular polymeric substance. Biofilms represent a prevalent mode of microbial life in natural, industrial and hospital settings. The microbial cells growing in a biofilm are physiologically distinct from planktonic cells of the same organism. Biofilm cells exhibit profound changes in gene expression and cell physiology compared with planctonic cells, and multiple genetic pathways mediate the regulation of biofilm formation. Microorganisms in biofilms form microbial colonies or condominiums that make it easy to carry out chemical reactions that are impossible for individual microbial cells. Biofilms can contain many different types of microorganism, e.g. bacteria, archaea, protozoa, fungi and algae.
The use of effective antimicrobial compositions to avoid biofilm formation is recommended for any surface in contact with water, such as swimming pool liners, water cooling surfaces, hoses, water dispensers, water storage and distribution systems for drinking water or aquaculture, and for surfaces of medical devices such as catheters, medical implants, wound dressings and the like, especially when intended for patients with metabolic disorders.
Biofilms are known to provide cells with an array of advantages as compared with planktonic cells including the ability to resist challenges from predators, antibiotics, disinfectants and host immune systems. Biofilms offer a selective advantage to a microorganism to ensure its survival, or allow it a certain amount of time to exist in a dormant state until suitable growth conditions arise which for instance provide bacteria protection from antibiotics and from a host's immune system. This causes serious problems and costs in medical, hospital and industrial settings.
Biofilms are believed to be involved in 80% of human bacterial infections such as periodontitis, gingivitis, urethritis, endocarditis, benign prostatic hyperplasia, chronic prostatitis, biliary tract infections, urinary tract infections, cystitis, lung infections, sinus infections, ear infections (e.g. otitis media, otitis externa), acne and other skin infections, rosacea, dental caries, dental plaque formation, nosocomial infections, open wounds, chronic wounds and device-associated infections. There is thus a need in the art to control biofilm formation. A biofilm inhibitor may be useful to clear the way for a bactericide to penetrate the affected cells and eradicate the infection or it can provide an alternative treatment approach for certain types of infections.
Biofilms can contribute to contaminating food (food industry), decreasing flow through pipelines by colonization of the pipe interior or mild steel corrosion (oil industry), initiating biofouling on vessel hulls (shipping industry), and infesting hospitals, in particular surgery rooms and medical devices used therein. Biofilm formation in combination with mineral deposition may reduce heat transfer in water based cooling plants There is thus also a need in the art for compounds and methods for preventing biofilm formation regulated mineral deposition. Valuable plants such as those producing fruits and vegetables, forestry crops, corn, cotton, rice, soybeans and wheat are affected in a deleterious manner by biofilm formation and hence need protection from biofilm formation.
US 2003/100593 teaches, but without biological evidence, that certain substituted 2-aminoimidazoles are useful for treating various diseases including cardiovascular disorders, Kaposi sarcoma, cancer, bacterial infections, migraine, allergy and osteoporosis.
WO 2009/070304 teaches 2-aminoimidazoles useful for controlling biofilms and bacterial infections in plants. WO 2009/123753 teaches 2-aminoimidazoles useful for inhibiting bacterial biofilms.
Organic Letters (2006) 8:5781-4 and J. Org. Chem. (2008) 73:6691-7 disclose a few imidazo[1,2-a]pyrimidinium salts as precursors of substituted 2-aminoimidazoles, but do not attribute any utility to these compounds.
J. Org. Chem. (1993) 58:3736-3741 and U.S. Patent Application Publication both describe methods for the synthesis of azidoalkylamines. The azide-alkyne Huisgen cycloaddition is a well known 1,3-dipolar cycloaddition method between an azide and a terminal or internal alkyne to provide a 1,2,3-triazole ring.
One object of the present invention is to address one or more of the above listed needs by providing efficient agents for reducing, controlling or inhibiting biofilm formation, such agents being either specifically acting on biofilm formation without influencing the planktonic growth of microorganisms, or being acting both on biofilm formation and planktonic growth in the same concentration range. Another object of the present invention is to provide new synthetic methods for producing such efficient biofilm formation inhibitors and precursors thereof.